Intraoperative hemispheric circulation time as a potential predictor of aneurysm occlusion after flow diverter treatment in large internal carotid artery aneurysm

Abstract

Intraoperative prediction of aneurysm occlusion after flow diverter (FD) placement may enable real-time adjustment of treatment strategies, such as adding an overlapping FD, to optimize efficacy outcomes. This study investigated whether the hemispheric circulation time (ΔHCT) calculated from intraoperative digital subtraction angiography (DSA) could serve as an intraoperative predictor of postprocedural aneurysm occlusion. Patients who underwent FD placement for large (≥ 10 mm) internal carotid artery (ICA) aneurysms without adjunctive coiling between January 2015 and December 2022 were retrospectively analyzed. ΔHCT was defined as the difference in contrast arrival time from the ICA horizontal intrapetrous segment to the superior sagittal sinus on lateral DSA before and after FD deployment. The relationship between ΔHCT and adequate occlusion (OKM grade C–D) at 1 year was evaluated. Seventy aneurysms were included. Adequate occlusion was achieved in 55 patients (78.6%) at 1 year. In univariate analysis, the change in ΔHCT following FD deployment was significantly higher in the adequate occlusion group than in the inadequate occlusion group (1.00 s vs. 0.25 s, p < 0.0001). ROC analysis yielded an area under the curve of 0.872 (95% CI, 0.777–0.967), with sensitivity of 0.83 and specificity of 0.80 for predicting adequate occlusion. Multivariable logistic regression analysis identified ΔHCT > 0.5 s as independently associated with adequate occlusion (odds ratio 20.2, 95% confidence interval 4.54–89.8, p = < 0.001). Intraoperative DSA-based ΔHCT analysis provides a practical and quantitative indicator for predicting aneurysm occlusion after FD placement in routine clinical practice.

Introduction

Flow diverter (FD) stents have markedly advanced the endovascular management of large and giant intracranial aneurysms by promoting intra-aneurysmal flow diversion and progressive thrombosis [1]. Nevertheless, a substantial proportion of aneurysms remain incompletely occluded after FD treatment, maintaining a risk of delayed rupture or need for retreatment [2]. Previous studies have reported complete occlusion rates of approximately 70–85% at 6–12 months, indicating that 15–30% of aneurysms fail to achieve adequate occlusion within the first year of follow-up [3–5].

Several studies have assessed flow modification as a means of providing feedback on treatment efficacy [6, 7]. Preoperative, intraoperative, and postoperative evaluations of hemodynamic modifications induced by FD placement has been explored using several modalities, including computational fluid dynamics, optical coherence tomography, and 4D-flow magnetic resonance imaging (MRI), to predict FD efficacy. Computational fluid dynamics can provide preoperative predictions of post-treatment flow changes; however, these simulations remain virtual and do not fully capture the actual hemodynamic alterations induced by FD deployment in vivo [8]. Optical coherence tomography can theoretically visualize flow-related changes and early neointimal reactions along the device; however, its clinical applicability is restricted by limited catheter navigability, making it difficult to visualize distal segments of the deployed stent in most intracranial locations [9]. Postoperative modalities such as 4D-flow MRI can provide highly detailed visualization of flow remodeling; however, they are performed only after treatment completion and therefore cannot contribute to intraoperative decision-making or alter procedural strategy [10]. These findings underscore the need for pragmatic intraoperative markers that are simple, reproducible, and readily applicable in daily clinical practice.

This study aimed to investigate whether the hemispheric circulation time (HCT) difference measured on standard lateral digital subtraction angiography (DSA) before and after FD deployment could serve as a practical and easily implemented alternative for the intraoperative assessment of flow diversion efficacy.

Materials and methods

This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Kohnan Hospital (approval number: 2023–0118-03). The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria were followed for reporting. The requirement for informed consent was waived because the analysis used anonymized clinical data obtained after each patient agreed to treatment and provided written consent. An opt-out approach approved by the Institutional Review Board was used, with notification provided through a publicly displayed poster.

Study design and patient cohort

In this observational cohort study, data were prospectively collected from consecutive patients with cerebral aneurysms who underwent FD deployment at our institution between January 2015 and December 2022. Patients were eligible for inclusion if they met the following criteria: (1) internal carotid artery (ICA) aneurysm, (2) aneurysm > 10 mm, or (3) first-time surgical intervention. Adjunctive coiling was generally performed in aneurysms considered at higher risk of delayed rupture, particularly intradural aneurysms measuring ≥ 15 mm. Because coil packing may alter intra-aneurysmal contrast dynamics and potentially affect HCT measurements, cases treated with FD combined with adjunctive coiling were excluded. Additional exclusion criteria included lack of angiographic follow-up at 1 year after FD deployment.

Angiographic follow-up using DSA was performed 1 year after FD placement. Aneurysm occlusion was graded according to the O’Kelly–Marotta (OKM) scale: A, total filling (> 95%); B, subtotal filling (5–95%); C, entry remnant (< 5%); or D, no filling (0%) [11]. Grades C–D were defined as adequate occlusion, and grades A-B were defined as inadequate occlusion. Patients were divided into two cohorts based on aneurysm occlusion status.

Definitions of branch involvement and aneurysm location

Branch involvement was defined as the presence of a branch vessel originating directly from the aneurysm dome. Aneurysm location was determined based on both MRI findings and angiographic morphology. First, the intra- versus extradural location was assessed using MRI; aneurysms located in the extradural space were classified as cavernous aneurysms. For intradural aneurysms, further subclassification was performed according to the direction of projection and the anatomical relationship to adjacent branches: aneurysms projecting medially were classified as superior hypophyseal artery aneurysms, those projecting laterally as lateral aneurysms, those arising from or involving the origin of the ophthalmic artery as ophthalmic artery aneurysms, and those involving the posterior communicating artery as posterior communicating artery aneurysms.

Interventional procedure

All patients received dual antiplatelet therapy consisting of 100 mg acetylsalicylic acid and 75 mg clopidogrel or 3.75 mg prasugrel daily, initiated at least two weeks before the procedure. Endovascular treatment was performed under general anesthesia using a standard triaxial system. Intravenous heparin was administered before device deployment to maintain an activated clotting time that was approximately twice the baseline value. Four types of flow diverters were used for aneurysm treatment: Surpass Streamline (Stryker Neurovascular, Fremont, CA, USA), Pipeline Flex (Medtronic, Irvine, CA, USA), Pipeline Shield (Medtronic, Irvine, CA, USA), and FRED (MicroVention, Aliso Viejo, CA, USA). The width and length of each FD were determined according to the parent vessel diameter and aneurysm neck width to ensure complete coverage. All devices were delivered through a 0.027-inch microcatheter using a standard deployment technique. Following FD deployment, cone-beam CT was performed to evaluate device apposition to the vessel wall, and additional balloon angioplasty was performed when necessary to improve apposition. Dual antiplatelet therapy was maintained for six months post-procedure, followed by single antiplatelet therapy for an additional six months.

Measurement of hemispheric circulation time (ΔHCT)

All angiographic procedures were performed using the Innova system (GE Healthcare, Buc, France) with the following parameters: matrix size, 750 × 750; field of view, 20 × 20 cm; and 2.5 frames/s. A total of 8 mL of iodinate contrast agent was injected at 6 mL/s. This protocol is identical to that used for conventional angiography at our institution [12]. Lateral projection DSA images of the ICA were acquired via selective ICA injection using a 6-Fr Simmons-type diagnostic catheter (Terumo, Tokyo, Japan) positioned in the cervical segment of the ICA, coaxially inserted into an 8-Fr Fubuki XF guiding catheter (Asahi Intecc, Aichi, Japan). To ensure consistency of hemodynamic assessment, angiography was performed from nearly identical catheter positions before and after FD deployment for HCT analysis. For each DSA imaging, a region of interest (ROI) was manually placed in the middle of the horizontal intrapetrous segment of the ICA and at the terminal portion of the superior sagittal sinus (SSS) (Fig. 1). All ROIs were drawn by two radiologic technicians masked to clinical condition.　Time–density curves were generated for each ROI using ImageJ software (National Institutes of Health, Bethesda, MD, USA). The time-density curve of each ROI was given as the mean of the optical density for all the pixels in the ROI. The timeto peak (TTP) was defined as the time from the onset of contrast opacification within the field of view to the maximum grayscale density on the time–density curve. The HCT was calculated as the difference between the TTP at the SSS and the TTP at the petrous ICA for both the pre- and post-FD runs.

Fig. 1.

Lateral projection digital subtraction angiography (DSA) image of the internal carotid artery (ICA). Regions of interest are manually placed on the middle of the ICA horizontal intrapetrous segment and at the terminal portion of the superior sagittal sinus to measure hemispheric circulation time (HCT) (arrows)

Finally, the HCT difference (ΔHCT) between the pre-FD (HCT pre) and post-FD (HCT post) of each patient was calculated with the following equations.

Statistical analysis

Continuous variables are summarized as medians with interquartile ranges, and categorical variables are presented as counts and percentages. Differences between groups were assessed using the Mann–Whitney U test for continuous variables and the chi-square or Fisher’s exact test for categorical variables. Multivariable logistic regression analysis was performed to identify factors independently associated with adequate occlusion, first adjusting for age as an underlying confounder. Next, an additional model was analyzed that further corrected for aneurysm size or branch involvement, both of which are associated with inadequate occlusion. A receiver operating characteristic (ROC) analysis was performed to evaluate the discriminative ability of ΔHCT. Statistical significance was set at p < 0.05. All statistical analyses were performed using R software (version 4.3.1; R Foundation for Statistical Computing, Vienna, Austria).

Results

Of the 107 patients with ICA aneurysms larger than 10 mm treated with FD for the first time in the respective time, a total of 70 patients treated were included in the analysis (Fig. 2 and Table 1). Based on angiographic outcomes at follow-up, patients were divided into the adequate occlusion group (n = 55, 78.6%) and the inadequate occlusion group (n = 15, 21.4%) (Table 2). In univariate analysis, most baseline characteristics, including sex, age, aneurysm size, neck size, number of devices, and presence of the eclipse sign, were not significantly associated with adequate occlusion at 1 year. In contrast, ΔHCT was significantly higher in the adequate occlusion group compared with the inadequate occlusion group (median 1.00 [interquartile range 0.75–1.62] vs. 0.25 [–0.25–0.25], p < 0.0001). Branch involvement was also associated with inadequate occlusion (p = 0.008), although the number of cases was small. ROC analysis demonstrated an area under the curve of 0.872 (95% CI, 0.777–0.967) for ΔHCT, with sensitivity of 0.83 and specificity of 0.80 for predicting adequate occlusion. The optimal cutoff value identified was 0.5 s. Representative cases are shown in Fig. 3. In the multivariable analyses after adjustment for age (Model 1), aneurysm size (Model 2), and branch involvement (Model 3), ΔHCT > 0.5 s remained independently associated with adequate occlusion, with odds ratios of 20.2 (95% confidence interval [CI] 4.54–89.8), 28.2 (95% CI 5.62–142), and 25.6 (95% CI 4.77–137), respectively (p < 0.001 for all) (Table 3). No other factors reached statistical significance in any of the multivariable models.

Fig. 2.

Flowchart showing the included and excluded patients with ICA aneurysms in this study (January 2015 to December 2022)

Table 1.

Baseline characteristics of the study cohort

	n = 70
Women	63 (90%)
Age (years)	65 (58–73)
Aneurysm location
Pcom	1 (1.4%)
Cavernous	59 (84.2%)
Oph	2 (2.8%)
SHA	3 (4.3%)
Lateral	5 (7.1%)
Aneurysm size (mm)	16.1 (12.3–19.3)
Neck size (mm)	8.1 (6.6–11.5)
Flow diverter
Surpass streamline	13 (18.6%)
Pipeline flex	35 (50%)
Pipeline shield	12 (17.1%)
FRED	10 (14.3%)
Number of FD
1	65 (90.9%)
2	5 (9.1%)
Vasospasm	0 (0%)
Eclipse sign	61 (87.1%)
Adequate occlusion	15 (21.4%)
Inadequate occlusion	55 (78.6%)
ΔHCT (s)	0.87 (0.25–1.43)

Values are presented as number (%) or median (interquartile range), as appropriate

PCom posterior communicating artery, Oph ophthalmic artery, SHA superior hypophyseal artery, FD flow diverter; FRED flow re-direction endoluminal device, ΔHCT change in hemispheric circulation time

Table 2.

Univariate analyses of factors associated with adequate occlusion at 1 year

	Adequate occlusion group (n = 55)	Inadequate occlusion group (n = 15)	p value
Women	50 (90.9%)	13 (86.7%)	0.637
Age > median	25 (45.5%)	11 (73,3%)	0.081
Aneurysm size > median	26 (47.2%)	9 (60%)	0.561
Neck size > median	30 (54.5%)	7 (46.7%)	0.771
Branch involvement	0 (0%)	3 (20%)	0.008
Number of FD
1	50 (90.9%)	15 (100%)	0.577
2	5 (9.1%)	0 (0%)	0.577
Eclipse sign	49 (89.1%)	12 (80%)	0.392
ΔHCT (s)	1 (0.75–1.62)	0.25 (−0.25–025)	< 0.0001

FD flow diverter, ΔHCT change in hemispheric circulation time, OR odds ratio, CI confidence interval

Fig. 3.

Representative cases. (A) A woman in her seventies with a left cavernous internal carotid artery (ICA) aneurysm (25 mm) treated with a Flow Re-Direction Endoluminal Device (FRED). In this case, the change in hemispheric circulation time (ΔHCT) remained 0 s. The angiographic outcome was O’Kelly–Marotta (OKM) grade A at one year after flow diverter (FD) deployment, indicating inadequate occlusion. (B) A woman in her seventies with a right cavernous ICA aneurysm (24 mm) treated with two Pipeline Shield devices. In this case, ΔHCT increased to 1.25 s. Consequently, the angiographic result was OKM grade D at one year after FD placement, indicating adequate occlusion

Table 3.

Multivariable analyses of factors associated with adequate occlusion at 1 year

	Multivariable analysis model 1		Multivariable analysis model 2		Multivariable analysis model 3
	OR (95% CI)	p value	OR (95% CI)	p value	OR (95% CI)	p value
Age > median	0.312 (0.07–1.4)	0.128
Aneurysm size > median			0.28 (006–1.36)	0.117
Branch involvement					4.06 × 10–9 (0-inf)	0.99
ΔHCT > 0.5 s	20.2 (4.54–89.8)	< 0.001	28.2 (5.62–142)	< 0.001	25.6 (4.77–137)	< 0.001

Model 1: Age and ΔHCT adjusted. Model 2: Aneurysm size and ΔHCT adjusted. Model 3: Branch involvement and ΔHCT adjusted

ΔHCT change in hemispheric circulation time, OR odds ratio, CI confidence interval

Discussion

In this study, intraoperative ΔHCT, a simple DSA-based hemodynamic indicator, was shown to be associated with aneurysm occlusion after FD treatment. Although baseline patient and aneurysm characteristics were largely comparable between the adequate and inadequate occlusion groups, ΔHCT demonstrated a clear and significant difference, emerging as the only independent factor associated with successful aneurysm occlusion in multivariable analysis. The diagnostic performance of ΔHCT was further supported by a high AUC of 0.872, indicating robust discriminatory ability. Taken together, these findings highlight the potential value of ΔHCT as a simple intraoperative physiological marker for predicting treatment efficacy in FD therapy.

Direct measurement and quantification of intra-aneurysmal flow alterations remain challenging because they depend on numerous factors, including imaging modality, ROI, vascular geometry, and device configuration [13]. Consequently, most hemodynamic evaluations rely on complex processing techniques that are impractical for real-time intraoperative decision-making. In contrast, flow changes in parent arteries can be assessed more readily because of their relatively simple and uniform anatomy. Large and giant intracranial aneurysms often develop intraluminal recirculation zones and regions of flow stagnation, which can impede antegrade ICA flow. [14] After treatment of large ICA aneurysms with FD, downstream perfusion frequently improves as the stagnant aneurysmal compartment is excluded and more physiological parent-artery flow is restored [15, 16]. Deployment of an FD across such aneurysms reconstructs parent-artery hemodynamics by reducing intra-aneurysmal inflow, attenuating stagnant flow zones, and reestablishing a streamlined laminar pattern within the ICA. Building on these insights, this study hypothesized that ICA flow measurements after FD placement would provide a practical, indirect assessment of intra-aneurysmal hemodynamic changes. In particular, a large ΔHCT after FD implantation reflects accelerated blood transit in the ICA, indicating effective flow diversion and reduced intra-aneurysmal inflow. Conversely, a minimal or absent ΔHCT suggests insufficient hemodynamic alteration and potentially incomplete aneurysm exclusion.

From a clinical standpoint, one of the most promising applications of intraoperative ΔHCT assessment lies in its ability to guide procedural strategy during FD implantation. When ΔHCT fails to show a sufficient increase after the initial device deployment, suggesting inadequate flow diversion, additional overlapping FDs or adjunctive coiling can be considered to further augment the hemodynamic effect. Overlapping FDs significantly enhance intra-aneurysmal flow reduction compared with a single device. Uchiyama et al. reported that two overlapping FDs reduced intra-aneurysmal velocity by more than 90%, whereas a single FD achieved only a 30% reduction, indicating a strong additive effect on inflow attenuation [17]. Similarly, Vranic et al. and Kim et al. showed that multiple FD constructs increase metal coverage density and decrease wall shear stress [18, 19]. In addition to device overlap, adjunctive coiling represents another strategy to enhance immediate flow stagnation and promote early aneurysm thrombosis. Although FD monotherapy relies on gradual hemodynamic remodeling, supplementary coiling can directly disrupt intra-aneurysmal recirculation zones, reduce inflow momentum, and lower wall stress, thereby mitigating the risk of delayed aneurysm rupture [20, 21]. Furthermore, intraoperative real-time ΔHCT monitoring provides a distinct clinical advantage. It allows immediate adjustment of the treatment strategy based on physiological response and avoids unnecessary device implantation, thereby reducing procedural complexity and minimizing the risk of device-related complications such as in-stent thrombosis, distal embolization, or branch occlusion. Considering that real-time DSA-based flow assessment requires only a few minutes for interpretation, this radiological biomarker represents a practical and objective tool for individualizing the degree of flow diversion required in each case, potentially improving both the safety and efficacy of FD therapy.

This study has several limitations. First, it was a retrospective, single-center study with a relatively small sample size, which may have limited the generalizability of the findings. Larger prospective studies are required to validate the predictive value of ΔHCT and to establish standardized thresholds for intraoperative decision-making. Second, ΔHCT was derived from two-dimensional DSA images, which provide only an indirect estimation of flow dynamics. Third, ΔHCT measurements may be influenced by variations in angiographic acquisition parameters, including frame rate, contrast injection rate, catheter position, and systemic hemodynamic factors. Standardization of acquisition protocols and normalization techniques would improve reproducibility across centers. Fourth, this study did not account for neointimal formation after FD placement. The therapeutic success of flow diversion depends not only on immediate hemodynamic modification but also on the subsequent biological healing process driven by endothelialization and neointimal maturation. Because ΔHCT captures only the hemodynamic component of aneurysm healing, it does not reflect the later tissue remodeling process. Fifth, although intraoperative ΔHCT assessment is associated with FD efficacy, it does not contribute to the preoperative selection of treatment modality. Ideally, a preoperative hemodynamic predictor would enable clinicians to identify patients who are unlikely to respond favorably to FD and allow consideration of alternative strategies, such as direct microsurgical clipping. Sixth, the applicability of ΔHCT may be limited to the aneurysm characteristics included in the present study. In particular, its applicability to aneurysms smaller than 10 mm or those located outside the ICA remains uncertain. Seventh, the ΔHCT values may be influenced not only by local aneurysmal hemodynamics but also by systemic factors such as cardiac output and blood pressure, and may therefore vary between individuals. Accordingly, direct comparison of ΔHCT values across patients should be interpreted with caution. However, because our analysis focused on ΔHCT rather than absolute HCT values, this approach may partially mitigate the influence of such systemic factors and may improve comparability across patients. Another limitation of this study is that treatment strategies were not modified based on intraoperative ΔHCT measurements. Therefore, we were unable to evaluate whether ΔHCT-guided decision-making, such as adjunctive coiling or additional FD placement, could improve treatment outcomes. Future studies are warranted to investigate the potential role of ΔHCT in guiding intraoperative treatment strategies. Finally, the follow-up angiographic and clinical data were limited to a relatively short period. Long-term studies are needed to determine whether ΔHCT-guided flow diversion strategies translate into improvements in clinical outcomes.

Conclusion

Intraoperative DSA-based ΔHCT analysis provides a practical and quantitative measure for predicting aneurysm occlusion following FD placement and for guiding real-time treatment decisions. Its straightforward application and immediate availability make it valuable for intraoperative assessment of FD efficacy in routine clinical practice.

Author contributions

Y.S and H.S. designed the study. Y.S., H.S., K.S., A.K. and S.O. collected the data. Y.S and H.S. performed the statistical analysis. Y.S and H.S. drafted the manuscript. H.E. provided critical review. All authors read and approved the final version of the manuscript.

Funding

This study was supported by a grant from the Japan Society for the Promotion of Science KAKENHI (grant number 23K08536).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Kohnan Hospital (approval number: 2023–0118-03).

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Competing interests

The authors declare no competing interests.

Clinical trial number

Not applicable.